Human immunodeficiency virus (HIV) is the etiological agent of acquired immunodeficiency syndrome (AIDS). At present there is no effective vaccine against this disease, and therapeutic agents provide only limited help. The objects of this project are to characterize HIV antigens, determine the targets of humoral and cell-mediated immunity, and to use this information to develop candidate vaccines. We have constructed recombinant vaccinia viruses containing genetic information of HIV and the closely related simian immunodeficiency virus (SIV). These recombinant viruses have been used to prepare purified proteins, make monoclonal antibodies, produce targets for cytotoxic T cells, study CD4- envelope interactions, and make candidate vaccines. We have continued to characterize a large panel of monoclonal antibodies that were produced against a novel soluble oligomeric form of the HIV-1 envelope protein. Of 35 mAbs directed against gp41, 21 preferentially reacted with oligomeric env. A subset of these mAbs reacted only with env oligomers. In contrast, only 1 of 27 mAbs directed against the gp120 subunit reacted more strongly with env oligomers than with monomers, and none were oligomer-specific. However, 50% of anti-gp120 mAbs preferentially recognized monomeric env, suggesting that some epitopes in gp120 are partially masked or altered by intersubunit contacts in the native env oligomer. The highly attenuated and host-restricted modified vaccinia virus Ankra (MVA) strain was used as a vector to express the simian immunodeficiency virus (SIV) envelope and gag-polymerase genes. Rhesus macaques were immunized with the live recombinant viruses and then challenged with an uncloned, homologous, cell free SIV. All immunized macaques exhibited a sustained, marked reduction of virus load in plasma, peripheral blood mononuclear cells, and lymph nodes compared to control animals.